Peroxynitrite decomposition catalyst: hemorrhagic shock

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This proposal is intended to establish a new therapeutic approach to save the lives of severely injured trauma victims with hemorrhagic shock (HS). In a small proportion of trauma, a fatal outcome is assured due to the irreversible loss of vital functions or massive blood loss. Frequently, however, emergent resuscitation is possible. These victims survive to hospitalization and are able to receive the full benefits of modern intensive care and surgery. In spite of fluid resuscitation and surgery to repair vascular and parenchymal injuries, however, not all treated patients survive HS. The principal impediment to a successful outcome in this population is the development of cardiovascular failure, a condition in which HS results in profound hypotension hypotension refractory to fluid replacement and inotropic support. There is substantial evidence that HS-induced tissue injury is mediated by profound alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion, and their reaction product peroxynitrite, a toxic oxidant. We are developing a novel metalloporphyrin that acts a speroxynitrite decomposition catalyst. Our lead compound, FP15, is dramatically protective in experimental models of ischemia-reperfusion injury. The central objective of this grant proposal is to establish that FP15 improves hemodynamics, metabolic function, end-organ injury, and survival in a rodent model of hemorrhagic shock. We will address this objective by characterizing the pharmacodynamic profile of FP15 in a rat model of severe fixed-pressure HS. We will correlate the cardiovascular (heart, rate, blood pressure), metabolic (serum lactate concentration), and survival dose-responses with serum FP15 concentrations, in order to establish a pharmacodynamic profile. The results of the present application will establish the technical merit and feasibility of FP15 as a novel parenteral therapeutic candidate for HS. PROPOSED COMMERCIAL APPLICATIONS: The annual domestic impact of hemorrhagic shock on the health care market is estimated at > $200 million. The worldwide market in hemorrhagic shock (developed countries only) is four times larger. Given the absence of a specific completely effective therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high-sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $800 million (annual).